tbuckley/cabot-search huggingface dataset:
Biosafety of mesoporous silica nanoparticles; towards clinical translation
Authors: Araceli Lérida-Viso, Alejandra Estepa-Fernández, Alba García-Fernández, Vicente Martí-Centelles, Ramón Martínez-Máñez
Journal: Advanced Drug Delivery Reviews (2023)

Mesoporous silica nanoparticles (MSNs) have attracted the attention of chemists, who have developed numerous systems for the encapsulation of a plethora of molecules, allowing the use of mesoporous silica nanoparticles for biomedical applications. MSNs have been extensively studied for their use in nanomedicine, in applications such as drug delivery, diagnosis, and bioimaging, demonstrating significant in vivo efficacy in different preclinical models. Nevertheless, for the transition of MSNs into clinical trials, it is imperative to understand the characteristics that make MSNs effective and safe. The biosafety properties of MSNs in vivo are greatly influenced by their physicochemical characteristics such as particle shape, size, surface modification, and silica framework. In this review, we compile the most relevant and recent progress in the literature up to the present by analyzing the contributions on biodistribution, biodegradability, and clearance of MSNs. Furthermore, the ongoing clinical trials and the potential challenges related to the administration of silica materials for advanced therapeutics are discussed. This approach aims to provide a solid overview of the state-of-the-art in this field and to encourage the translation of MSNs to the clinic.
Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial
Authors: James Chih-Hsin Yang, Geoffrey Liu, Shun Lu, Jianxing He, Mauricio Burotto, Myung-Ju Ahn, Dong-Wan Kim, XiaoQing Liu, Yanqiu Zhao, Sylvie Vincent, Jiani Yin, Xin Ma, Huamao M. Lin, Sanjay Popat
Journal: Journal of Thoracic Oncology (2023)

This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib.Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events.The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0-16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee-assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66-1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32-0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%).Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3.
Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right‐to‐left shunt‐induced hypoxia
Authors: Bosi Dong, Ying Lu, Siyu He, Baichuan Li, Yajiao Li, Qi Lai, Wanling Li, Shuming Ji, Yucheng Chen, Lunzhi Dai, Lei Chen
Journal: MedComm (2023)

Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right-to-left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty-eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO-caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS-induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.
Clinical evaluation of a multitarget fecal immunochemical test‐sDNA test for colorectal cancer screening in a high‐risk population: a prospective, multicenter clinical study
Authors: Ye‐Ting Hu, Xiao‐Feng Chen, Chun‐Bao Zhai, Xiao‐Tian Yu, Gang Liu, Zhi‐Guo Xiong, Zi‐Qiang Wang, San‐Jun Cai, Wen‐Cai Li, Xiang‐Xing Kong, Qian Xiao, Cai‐Hua Wang, Zhi‐Hua Tao, Li‐Yun Niu, Jian‐Long Men, Qing Wang, Shao‐Zhong Wei, Jun‐Jie Hu, Ting‐Han Yang, Jun‐Jie Peng, Guo‐Zhong Jiang, Ning Lv, Yi‐You Chen, Shu Zheng, Yan‐Hong Gu, Ke‐Feng Ding
Journal: MedComm (2023)

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (
CYP19A1 mediates severe SARS-CoV-2 disease outcome in males
Authors: Stephanie Stanelle-Bertram, Sebastian Beck, Nancy Kouassi Mounogou, Berfin Schaumburg, Fabian Stoll, Amirah Al Jawazneh, Zoé Schmal, Tian Bai, Martin Zickler, Georg Beythien, Kathrin Becker, Madeleine de la Roi, Fabian Heinrich, Claudia Schulz, Martina Sauter, Susanne Krasemann, Philine Lange, Axel Heinemann, Debby van Riel, Lonneke Leijten, Lisa Bauer, Thierry P.P. van den Bosch, Boaz Lopuhaä, Tobias Busche, Daniel Wibberg, Dirk Schaudien, Torsten Goldmann, Anna Lüttjohann, Jenny Ruschinski, Hanna Jania, Zacharias Müller, Vinicius Pinho dos Reis, Vanessa Krupp-Buzimkic, Martin Wolff, Chiara Fallerini, Margherita Baldassarri, Simone Furini, Katrina Norwood, Christopher Käufer, Nina Schützenmeister, Maren von Köckritz-Blickwede, Maria Schroeder, Dominik Jarczak, Axel Nierhaus, Tobias Welte, Stefan Kluge, Alice C. McHardy, Frank Sommer, Jörn Kalinowski, Susanne Krauss-Etschmann, Franziska Richter, Jan von der Thüsen, Wolfgang Baumgärtner, Karin Klingel, Benjamin Ondruschka, Alessandra Renieri, Gülsah Gabriel
Journal: Cell Reports Medicine (2023)

Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n = 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment.
Targeting autophagy and beyond: Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy
Authors: Jing Ye, Jin Zhang, Yanghui Zhu, Lian Wang, Xian Jiang, Bo Liu, Gu He
Journal: Acta Pharmaceutica Sinica B (2023)

Beclin-1 is the firstly-identified mammalian protein of the autophagy machinery, which functions as a molecular scaffold for the assembly of PI3KC3 (class III phosphatidylinositol 3 kinase) complex, thus controlling autophagy induction and other cellular trafficking events. Notably, there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes, including tumor suppression and progression as well as resistance to cancer therapeutics and CSC (cancer stem-like cell) maintenance. More importantly, Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers. In this review, we provide a comprehensive survey of the structure, functions, and regulations of Beclin-1, and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology. Moreover, we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy, providing novel insights into a promising strategy for regulating Beclin-1 to improve cancer therapeutics in the future.
Hepatocellular Carcinoma Surveillance Patterns and Outcomes in Patients With Cirrhosis
Authors: Darine Daher, Karim Seif El Dahan, Alva Cano, Michael Gonzales, Crystal Ransom, Erik Jaurez, Osiris Carranza, Lisa Quirk, Todd Morgan, Purva Gopal, Madhukar S. Patel, Sarah Lieber, Jeremy Louissaint, Thomas G. Cotter, Lisa B. VanWagner, Ju Dong Yang, Neehar D. Parikh, Adam Yopp, Nicole E. Rich, Amit G. Singal
Journal: Clinical Gastroenterology and Hepatology (2023)
Risk assessment according to IPSS-M is superior to AML ELN risk classification in MDS/AML overlap patients defined by ICC
Authors: Sandra Huber, Constance Baer, Stephan Hutter, Frank Dicker, Irene Fuhrmann, Manja Meggendorfer, Christian Pohlkamp, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach, Gregor Hoermann
Journal: Leukemia (2023)
A Combination of BRAF and EZH1/SPOP/ZNF148 Three-Gene Mutational Classifier Improves Benign Call Rate in Indeterminate Thyroid Nodules
Authors: Shichen Xu, Gangming Cai, Yun Zhu, Xiaobo Gu, Jing Wu, Xian Cheng, Jiandong Bao, Huixin Yu, Li Zhang
Journal: Endocrine Pathology (2023)
Burrow Ink Test for Scabies
Authors: Daan Rauwerdink, Deepak Balak
Journal: New England Journal of Medicine (2023)

A 20-year-old man presented with a 3-month history of itchiness. Papules were seen on the trunk, wrists, and genital area. A wrist lesion was covered with a purple skin marker and then wiped with alcohol, revealing a skin burrow.
Correction: CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma
Authors: Jinpeng Du, Tian Lan, Haotian Liao, Xuping Feng, Xing Chen, Wenwei Liao, Guimin Hou, Lin Xu, Qingbo Feng, Kunlin Xie, Mingheng Liao, Xiangzheng Chen, Jiwei Huang, Kefei Yuan, Yong Zeng
Journal: Molecular Cancer (2023)

attention that the image in Fig. 6F (the HuCCT1-sicNFIB group) appears to be doubled over itself possibly caused by an error during the microscopic image acquisition process.
Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy
Authors: Mengke Niu, Ming Yi, Yuze Wu, Lijuan Lyu, Qing He, Rui Yang, Liang Zeng, Jian Shi, Jing Zhang, Pengfei Zhou, Tingting Zhang, Qi Mei, Qian Chu, Kongming Wu
Journal: Journal of Hematology & Oncology (2023)

Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators of antitumor immunity, like TGF-β and VEGFA, are also involved in immune escape of tumor cells and induce immunotherapy resistance.We developed a novel anti-TGF-β/VEGF bispecific antibody Y332D based on the Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting and transwell assays were used to measure the biological activities of the anti-TGF-β moiety. The NFAT luciferase reporter assay, luminescent cell viability assay and tube formation assay were used to measure the biological activities of the anti-VEGF moiety. The in vivo anticancer efficacy of Y332D alone or in combination with PD-1 blockade was evaluated in H22, EMT-6, 4T1, and AKT/Ras-driven murine hepatocellular carcinoma tumor models. Immunofluorescent staining, flow cytometry, RNA-seq and quantitative RT-PCR were adopted to analyze the alterations in the tumor microenvironment.Y332D could maintain specific binding affinities for TGF-β and VEGFA. Y332D almost entirely counteracted the in vitro biological functions of TGF-β and VEGFA, including immunosuppression, activated TGF-β signaling, epithelial-mesenchymal transition (EMT), activated VEGF/VEGFR signaling, HUVEC proliferation and tube formation. The in vivo experiment data demonstrated that Y332D was more effective in inhibiting tumor growth and metastasis than anti-TGF-β and anti-VEGF monotherapies. In combination therapies, Y332D plus PD-1 blockade exhibited the most potent and durable anticancer effect. Mechanistically, Y332D plus PD-1 blockade upregulated the density and function of tumor-infiltrating lymphocytes and exerted reinvigorated antitumor immunity.Y332D could simultaneously block TGF-β and VEGF signalings. In comparison with the monotherapies, Y332D combined with PD-1 blockade exerts superior antitumor effect through improving immune microenvironment.
Facial amphiphilic naphthoic acid-derived antimicrobial polymers against multi-drug resistant gram-negative bacteria and biofilms
Authors: Leman Buzoglu Kurnaz, Swagatam Barman, Xiaoming Yang, Claire Fisher, F. Wayne Outten, Prakash Nagarkatti, Mitzi Nagarkatti, Chuanbing Tang
Journal: Biomaterials (2023)
The Cancer Moonshot Immuno-Oncology Translational Network at 5: accelerating cancer immunotherapies
Authors: Ananth Annapragada, Andrew G Sikora, Himangi Marathe, Song Liu, Michael Demetriou, Lawrence Fong, Jinming Gao, Donald Kufe, Zachary S Morris, Eduardo Vilar, Elad Sharon, Alan Hutson, Kunle Odunsi
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract The Immuno-Oncology Translational Network (IOTN) was established in 2018 as part of the Cancer Moonshot. In 2022, President Joe Biden set new goals to reduce the cancer death rate by half within 25 years and improve the lives of people with cancer and cancer survivors. The IOTN is focused on accelerating translation of cancer immunology research, from bench to bedside, and improving immunotherapy outcomes across a wide array of cancers in the adult population. The unique structure and team science approach of the IOTN is designed to accelerate discovery and evaluation of novel immune-based therapeutic and prevention strategies. In this article, we describe IOTN progress to date, including new initiatives and the development of a robust set of resources to advance cancer immunology research. We summarize new insights by IOTN researchers, some of which are ripe for translation for several types of cancers. Looking to the future, we identify barriers to the translation of immuno-oncology concepts into clinical trials and key areas for action and improvements that are suitable for high-yield investments. Based on these experiences, we recommend novel National Institutes of Health funding mechanisms and development of new resources to address these barriers.
Development and preclinical evaluation of multifunctional hydrogel for precise thermal protection during thermal ablation
Authors: Bowen Zheng, Peng Zhang, Qijun Lv, Tao Wu, Yadong Liu, Junjie Tang, Yanping Ma, Lili Cheng, Langtao Xu, Yizhen Wang, Yifan Xue, Jie Liu, Jie Ren
Journal: Bioactive Materials (2023)

Image-guided thermal ablation (TA), which is less invasive, has been widely applied for treating various kinds of tumors. However, TA still poses the potential risk of thermal damage to sensitive tissue nearby. Therefore, an adjunctive thermoprotective hydrodissection technique with constant injection of 5% glucose (5% Glu) has currently been adopted for clinical application, but this may be hazardous to humans. In this study, a multifunctional hyaluronic acid-based hydrogel (HA-Dc) was developed for hydrodissection. Compared with 5% Glu (the most clinically used solution) and the previously reported F127 hydrogel, the HA-Dc hydrogel was studied in vitro in a porcine liver model and in vivo in a rabbit model and showed good injectability and better tissue retention, stability, and thermoprotective properties throughout the TA procedure. Furthermore, in the preclinical evaluation in a Macaca fascicularis (M. fascicularis) model, HA-Dc showed excellent performance in terms of stricter neuroprotection compared with 5% Glu. In addition, the HA-Dc hydrogel with good biocompatibility and controllable degradation behavior in vivo could be a promising platform for thermal protection during clinical TA procedures.
Multiphasic bone-ligament-bone integrated scaffold enhances ligamentization and graft-bone integration after anterior cruciate ligament reconstruction
Authors: Xianrui Xie, Jiangyu Cai, Dan Li, Yujie Chen, Chunhua Wang, Guige Hou, Thorsten Steinberg, Bernd Rolauffs, Mohamed EL-Newehy, Hany EL-Hamshary, Jia Jiang, Xiumei Mo, Jinzhong Zhao, Jinglei Wu
Journal: Bioactive Materials (2023)

The escalating prevalence of anterior cruciate ligament (ACL) injuries in sports necessitates innovative strategies for ACL reconstruction. In this study, we propose a multiphasic bone-ligament-bone (BLB) integrated scaffold as a potential solution. The BLB scaffold comprised two polylactic acid (PLA)/deferoxamine (DFO)@mesoporous hydroxyapatite (MHA) thermally induced phase separation (TIPS) scaffolds bridged by silk fibroin (SF)/connective tissue growth factor (CTGF)@Poly(l-lactide-co-ε-caprolactone) (PLCL) nanofiber yarn braided scaffold. This combination mimics the native architecture of the ACL tissue. The mechanical properties of the BLB scaffolds were determined to be compatible with the human ACL. In vitro experiments demonstrated that CTGF induced the expression of ligament-related genes, while TIPS scaffolds loaded with MHA and DFO enhanced the osteogenic-related gene expression of bone marrow stem cells (BMSCs) and promoted the migration and tubular formation of human umbilical vein endothelial cells (HUVECs). In rabbit models, the BLB scaffold efficiently facilitated ligamentization and graft-bone integration processes by providing bioactive substances. The double delivery of DFO and calcium ions by the BLB scaffold synergistically promoted bone regeneration, while CTGF improved collagen formation and ligament healing. Collectively, the findings indicate that the BLB scaffold exhibits substantial promise for ACL reconstruction. Additional investigation and advancement of this scaffold may yield enhanced results in the management of ACL injuries.
Advances in the engineering of the outer blood-retina barrier: From in-vitro modelling to cellular therapy
Authors: Chloé Dujardin, Walter Habeler, Christelle Monville, Didier Letourneur, Teresa Simon-Yarza
Journal: Bioactive Materials (2023)

The outer blood-retina barrier (oBRB), crucial for the survival and the proper functioning of the overlying retinal layers, is disrupted in numerous diseases affecting the retina, leading to the loss of the photoreceptors and ultimately of vision. To study the oBRB and/or its degeneration, many in vitro oBRB models have been developed, notably to investigate potential therapeutic strategies against retinal diseases. Indeed, to this day, most of these pathologies are untreatable, especially once the first signs of degeneration are observed. To cure those patients, a current strategy is to cultivate in vitro a mature oBRB epithelium on a custom membrane that is further implanted to replace the damaged native tissue. After a description of the oBRB and the related diseases, this review presents an overview of the oBRB models, from the simplest to the most complex. Then, we propose a discussion over the used cell types, for their relevance to study or treat the oBRB. Models designed for in vitro applications are then examined, by paying particular attention to the design evolution in the last years, the development of pathological models and the benefits of co-culture models, including both the retinal pigment epithelium and the choroid. Lastly, this review focuses on the models developed for in vivo implantation, with special emphasis on the choice of the material, its processing and its characterization, before discussing the reported pre-clinical and clinical trials.
Enhancement of Microglia Functions by Developed Nano‐Immuno‐Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment
Authors: Minjun Xu, Yunlong Cheng, Ran Meng, Peng Yang, Jian Chen, Zhen Qiao, Jing Wu, Kang Qian, Yixian Li, Pengzhen Wang, Lingling Zhou, Tianying Wang, Dongyu Sheng, Qizhi Zhang
Journal: Advanced Healthcare Materials (2023)

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.